Mechanistic study of nonivamide enhancement of hyperthermia-induced apoptosis in U937 cells

Abstract

Hyperthermia is one therapeutic tool for damaging and killing cancer cells, with minimal injury to normal tissues. However, its cytotoxic effects alone are insufficient for quantitative cancer cell death. To overcome this limitation, several studies have explored non-toxic enhancers for hyperthermia-induced cell death. Capsaicin may be applicable as a therapeutic tool against various types of cancer. In the present study, we employed nonivamide, a less-pungent capsaicin analogue, to investigate its possible enhancing effects on hyperthermia-induced apoptosis; moreover, we analyzed its molecular mechanism. Treatment of U937 cells at 44 °C for 15 min, combined with nonivamide 50 μM, revealed enhancement of apoptosis. Significant increases in reactive oxygen species generation, mitochondrial dysfunction, and cleaved caspase-3 were observed during the combined treatment; these were accompanied by an increase in pro-apoptotic Bcl-2 family proteins and a decrease in anti-apoptotic Bcl-2 proteins. In addition, significant increases in p-JNK and p-p38 were detected, following the combined treatment. In conclusion, nonivamide enhanced hyperthermia-induced apoptosis via a mitochondrial-caspase dependent pathway. The underlying mechanism may include elevation of intracellular reactive oxygen species, mitochondrial dysfunction, and increased activation of JNK and p38.

Ethanol Enhances Hyperthermia-Induced Cell Death in Human Leukemia Cells

“…Thus, targeting Mcl-1 has been considered as a promising approach for cancer treatment since its overexpression has been widely reported in both hematological and solid tumors [ 39 , 62 , 63 , 64 ]. In contrast, levels of other anti-apototic factors like Bcl-2 and Bcl-xL and the pro-apoptotic factor Bax were not altered by hyperthermia—which is in agreement with previous studies [ 25 , 65 , 66 ]—and combination of hyperthermia plus ethanol did not change the expression pattern of these proteins. The total amount of Bax was not affected by ethanol; however, there was a clear reduction in its cytosolic levels, which suggests translocation to the mitochondria to promote the permeability of this organelle.…”

“…Nanoparticles with appropriate external energy sources are being used for local treatment [ 45 , 46 , 47 ]. Strategies to enhance the therapeutic efficacy of hyperthermia are also under investigation; in this context cytotoxic properties of hyperthermia on leukemia, melanoma, lung carcinoma, and colon cancer cells, among others, have been improved by the use of compounds that sensitize to the cells [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. In the present study the effect of ethanol on cytotoxicity exhibited by hyperthermia on leukemia cells was investigated since this alcohol has been reported to enhance the antitumor properties of radiation and the effectiveness of chemotherapeutic agents like TRAIL [ 29 , 30 , 31 , 32 , 34 ].…”

“…Consequently, the possibility to reduce thermotolerance by using low toxicity compounds is of great clinical importance. In this regard, several studies in vivo and in vitro have explored non-toxic enhancers for hyperthermia-induced cell death in a variety of human cancer cells including lung cancer [ 19 , 20 ], colon cancer [ 21 , 22 ], melanoma [ 23 ], and leukemia cells [ 24 , 25 , 26 , 27 ].…”

Nanomagnetite-embedded PLGA Spheres for Multipurpose Medical Applications

“…The PLGA-Fe 3 O 4 -IBUP solutions, obtained by dispersing ~14 mg of lyophilized microspheres in deionized water, were introduced into the Dewar vial and subjected to three magnetic fields, with powers representing 60%, 80%, and 100% from the maximum output power. The temperature evolution of each sample was recorded up to 50 °C (slightly above the 42–45 °C temperature range associated with the occurrence of apoptosis and necrosis of cancer cells) [49,86,87] by using an optical fiber supplied with a TS4 sensor (precision ± 0.2 °C) from Optocon (Dresden, Germany) connected to a PC. In all experiments, deionized water was used as blank specimen.…”

Dithiol‐Activated Bioorthogonal Chemistry for Endoplasmic Reticulum‐Targeted Synergistic Chemophototherapy

“…[30] Recently, several lines of studies reveal that capsaicin and nonivamide display strong antineoplastic activity in a wide array of human cancer cells via multiple mechanisms like induction of ROS and RNS, inhibition of NADH oxidase activity and mitochondrial respiration, and serious ER stress. [31][32][33] The pharmacological activity of capsaicin and nonivamide is highly dependent on its concentration in target tissues. [34][35][36] However, the severe burning sensation from treatment limits the level of drug dose.…”